Designed PKC-targeting bryostatin analogs modulate innate immunity and neuroinflammation

Efrat Abramson; Clayton Hardman; Akira J Shimizu; Soonmyung Hwang; Lynda D Hester; Solomon H Snyder; Paul A Wender; Paul M Kim; Michael D Kornberg

doi:10.1016/j.chembiol.2020.12.015

Designed PKC-targeting bryostatin analogs modulate innate immunity and neuroinflammation

Cell Chem Biol. 2021 Apr 15;28(4):537-545.e4. doi: 10.1016/j.chembiol.2020.12.015. Epub 2021 Jan 19.

Authors

Efrat Abramson¹, Clayton Hardman², Akira J Shimizu², Soonmyung Hwang¹, Lynda D Hester³, Solomon H Snyder⁴, Paul A Wender², Paul M Kim⁵, Michael D Kornberg⁶

Affiliations

¹ Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA.
² Departments of Chemistry and of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
³ Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA.
⁴ Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD 21205, USA.
⁵ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD 21287, USA. Electronic address: pmkim@jhmi.edu.
⁶ Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA. Electronic address: michael.kornberg@jhmi.edu.

Abstract

Neuroinflammation characterizes multiple neurologic diseases, including primary inflammatory conditions such as multiple sclerosis and classical neurodegenerative diseases. Aberrant activation of the innate immune system contributes to disease progression, but drugs modulating innate immunity, particularly within the central nervous system (CNS), are lacking. The CNS-penetrant natural product bryostatin-1 attenuates neuroinflammation by targeting innate myeloid cells. Supplies of natural bryostatin-1 are limited, but a recent scalable good manufacturing practice (GMP) synthesis has enabled access to it and its analogs (bryologs), the latter providing a path to more efficacious, better tolerated, and more accessible agents. Here, we show that multiple synthetically accessible bryologs replicate the anti-inflammatory effects of bryostatin-1 on innate immune cells in vitro, and a lead bryolog attenuates neuroinflammation in vivo, actions mechanistically dependent on protein kinase C (PKC) binding. Our findings identify bryologs as promising drug candidates for targeting innate immunity in neuroinflammation and create a platform for evaluation of synthetic PKC modulators in neuroinflammatory diseases.

Keywords: EAE; PKC; bryolog; bryostatin; innate immunity; microglia; multiple sclerosis; neuroinflammation; prostratin.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bryostatins / chemical synthesis
Bryostatins / chemistry
Bryostatins / pharmacology*
Drug Design*
Female
Immunity, Innate / drug effects*
Immunity, Innate / immunology
Inflammation / drug therapy*
Inflammation / immunology
Mice
Mice, Inbred C57BL
Molecular Conformation
Pregnancy
Protein Kinase C-delta / antagonists & inhibitors*
Protein Kinase C-delta / metabolism
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Stereoisomerism

Substances

Bryostatins
Protein Kinase Inhibitors
bryostatin 1
Prkcd protein, mouse
Protein Kinase C-delta

Abstract

Publication types

MeSH terms

Substances

Grants and funding